Reduced Usage of GLS Intronic Polyadenylation Promotes Cellular Senescence

Alternative polyadenylation (APA) of mRNA is a widespread transcriptomic mechanism which fine-tunes gene expression and plays important roles in diverse biological processes. Of the different APA types, intronic polyadenylation is a prevalent but not well understood one. Although the upstream regulation of intronic polyadenylation is extensively investigated, the understanding of its biological function largely lags behind. Here, we discovered that intronic polyadenylation of glutaminase-encoding gene Glutaminase (GLS) generated an isoform termed Glutaminase C (GAC, encoding glutaminase C), which played regulatory roles in cellular senescence, the basis of individual aging and also an important anti-cancer mechanism. Reduced usage of GLS intronic polyadenylation (pA) site was consistent in both human and mouse senescence models. GAC protein mainly located in mitochondria, and downregulation of GAC induced cellular senescence in both human and mouse cells. Increased reactive oxygen species (ROS) level and decreased ATP synthesis explained the senescence-associated phenotypes in GAC deficient cells. Polyadenylation factor CPSF6 bound to the last exon of GAC to regulate its expression. Rescue experiment confirmed that CPSF6-GAC signal axis did play important roles in regulating cellular senescence. Together, the present study demonstrated for the first time that intronic polyadenylation could regulate cellular senescence, largely extending our understanding of the biological roles of intronic polyadenylation.

The online version contains supplementary material available at 10.1007/s43657-024-00198-2.